American Urological Association - Treatment of Non-Metastatic Muscle-Invasive Bladder Cancer: AUA/ASCO/ASTRO/SUO Guideline

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Treatment of Non-Metastatic Muscle-Invasive Bladder Cancer: AUA/ASCO/ASTRO/SUO Guideline

Published 2017

Treatment of Non-Metastatic Muscle-Invasive Bladder Cancer: AUA/ASCO/ASTRO/SUI Guideline provides a clinical framework for the management of muscle-invasive urothelial bladder cancer. Topics covered include patient evaluation and counseling, as well as an in-depth discussion of treatment options, including chemotherapy, cystectomy, urinary diversion, lymphadenectomy, and variou bladder preserving treatment options.

Unabridged version of this Guideline [pdf]
Algorithm associated with this Guideline [pdf]
Presentation from the 2017 Annual Meeting [pdf]

Panel Members

Sam S. Chang, MD, MBA; Bernard H. Bochner, MD, FACS; Roger Chou, MD; Robert Dreicer, MD, MS, MACP, FASCO; Ashish M. Kamat, MD, MBBS, FACS; Seth P. Lerner, MD, FACS; Yair Lotan, MD; Joshua J. Meeks, MD, PhD; Jeff M. Michalski, MD, MBA; Todd M. Morgan, MD; Diane Z. Quale; Jonathan E. Rosenberg, MD; Anthony L. Zietman, MD; Jeffrey M. Holzbeierlein, MD, FACS

Executive Summary

Purpose

Although representing approximately 25% of patients diagnosed with bladder cancer, muscle-invasive bladder cancer (MIBC) carries a significant risk of death that has not significantly changed in decades. Increasingly, clinicians and patients recognize the importance of multidisciplinary collaborative efforts that take into account survival and quality of life (QOL) concerns. For the first time for any type of malignancy, the American Urological Association (AUA), the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO), and the Society of Urologic Oncology (SUO) have formulated an evidence-based guideline. This guideline provides a risk-stratified clinical framework for the management of muscle-invasive urothelial bladder cancer and is designed to be used in conjunction with the associated treatment algorithm.

Methodology

The systematic review utilized to inform this guideline was conducted by a methodology team at the Pacific Northwest Evidence-based Practice Center. The original review was funded by the Agency for Healthcare Research and Quality (AHRQ), and a subsequent supplemental report was funded by the AUA to address additional key questions and more recently published literature. A research librarian experienced in conducting literature searches for comparative effectiveness reviews searched in Ovid MEDLINE® (January 1990 to October 2014), the Cochrane Central Register of Controlled Trials (through September 2014), the Cochrane Database of Systematic Reviews (through September 2014), Health Technology Assessments (through Third Quarter 2014), the National Health Sciences Economic Evaluation Database (through Third Quarter 2014), and the Database of Abstracts of Reviews of Effects (through Third Quarter 2014) to capture published and gray literature. The methodology team searched for unpublished studies in clinical trial registries (ClinicalTrials.gov, Current Controlled Trials, ClinicalStudyResults.org and the World Health Organization International Clinical Trials Registry Platform) and regulatory documents (Drugs@FDA.gov and FDA Medical Devices Registration and Listing). A supplemental search of Ovid MEDLINE and Cochrane Central Register of Controlled Trials was conducted to capture additional published literature through February 2, 2016. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high), B (moderate) or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions. 

Guideline Statements

Initial Patient Evaluation and Counseling

  1. Prior to treatment consideration, a full history and physical exam should be performed, including an exam under anesthesia, at the time of transurethral resection of bladder tumor for a suspected invasive cancer. (Clinical Principle)
  2. Prior to muscle-invasive bladder cancer management, clinicians should perform a complete staging evaluation, including imaging of the chest and cross sectional imaging of the abdomen and pelvis with intravenous contrast if not contraindicated. Laboratory evaluation should include a comprehensive metabolic panel (complete blood count, liver function tests, alkaline phosphatase, and renal function). (Clinical Principle)
  3. An experienced genitourinary pathologist should review the pathology of a patient when variant histology is suspected or if muscle invasion is equivocal (e.g., micropapillary, nested, plasmacytoid, neuroendocrine, sarcomatoid, extensive squamous or glandular differentiation). (Clinical Principle)
  4. For patients with newly diagnosed muscle-invasive bladder cancer, curative treatment options should be discussed before determining a plan of therapy that is based on both patient comorbidity and tumor characteristics. Patient evaluation should be completed using a multidisciplinary approach. (Clinical Principle)
  5. Prior to treatment, clinicians should counsel patients regarding complications and the implications of treatment on quality of life (e.g., impact on continence, sexual function, fertility, bowel dysfunction, metabolic problems). (Clinical Principle)

Treatment

Neoadjuvant/Adjuvant Chemotherapy

  1. Utilizing a multidisciplinary approach, clinicians should offer cisplatin-based neoadjuvant chemotherapy to eligible radical cystectomy patients prior to cystectomy. (Strong Recommendation; Evidence Level: Grade B)
  2. Clinicians should not prescribe carboplatin-based neoadjuvant chemotherapy for clinically resectable stage cT2-T4aN0 bladder cancer. Patients ineligible for cisplatin-based neoadjuvant chemotherapy should proceed to definitive locoregional therapy. (Expert Opinion)
  3. Clinicians should perform radical cystectomy as soon as possible following a patient’s completion of and recovery from neoadjuvant chemotherapy. (Expert Opinion)
  4. Eligible patients who have not received cisplatin-based neoadjuvant chemotherapy and have non-organ confined (pT3/T4and/or N+) disease at cystectomy should be offered adjuvant cisplatin-based chemotherapy. (Moderate Recommendation; Evidence Level: Grade C)

Radical Cystectomy

  1. Clinicians should offer radical cystectomy with bilateral pelvic lymphadenectomy for surgically eligible patients with resectable non-metastatic (M0) muscle-invasive bladder cancer. (Strong Recommendation; Evidence Level: Grade B)
  1. When performing a standard radical cystectomy, clinicians should remove the bladder, prostate, and seminal vesicles in males and should remove the bladder, uterus, fallopian tubes, ovaries, and anterior vaginal wall in females. (Clinical Principle)
  2. Clinicians should discuss and consider sexual function preserving procedures for patients with organ-confined disease and absence of bladder neck, urethra, and prostate (male) involvement. (Moderate Recommendation; Evidence Level: Grade C)

Urinary Diversion

  1. In patients undergoing radical cystectomy, ileal conduit, continent cutaneous, and orthotopic neobladder urinary diversions should all be discussed. (Clinical Principle)
  2. In patients receiving an orthotopic urinary diversion, clinicians must verify a negative urethral margin. (Clinical Principle)

Perioperative Surgical Management

  1. Clinicians should attempt to optimize patient performance status in the perioperative setting. (Expert Opinion)
  2. Perioperative pharmacologic thromboembolic prophylaxis should be given to patients undergoing radical cystectomy. (Strong Recommendation; Evidence Level: Grade B)
  3. In patients undergoing radical cystectomy µ -opioid antagonist therapy should be used to accelerate gastrointestinal recovery, unless contraindicated. (Strong Recommendation; Evidence Level: Grade B)
  4. Patients should receive detailed teaching regarding care of urinary diversion prior to discharge from the hospital. (Clinical Principle)

Pelvic Lymphadenectomy

  1. Clinicians must perform a bilateral pelvic lymphadenectomy at the time of any surgery with curative intent. (Strong Recommendation; Evidence Level: Grade B)
  2. When performing bilateral pelvic lymphadenectomy, clinicians should remove, at a minimum, the external and internal iliac and obturator lymph nodes (standard lymphadenectomy). (Clinical Principle)

Bladder Preserving Approaches

Patient Selection

  1. For patients with newly diagnosed non-metastatic muscle-invasive bladder cancer who desire to retain their bladder, and for those with significant comorbidities for whom radical cystectomy is not a treatment option, clinicians should offer bladder preserving therapy when clinically appropriate. (Clinical Principle)
  2. In patients under consideration for bladder preserving therapy, maximal debulking transurethral resection of bladder tumor and assessment of multifocal disease/carcinoma in situ should be performed. (Strong Recommendation; Evidence Level: Grade C)

Maximal TURBT and Partial Cystectomy

  1. Patients with muscle-invasive bladder cancer who are medically fit and consent to radical cystectomy should not undergo partial cystectomy or maximal transurethral resection of bladder tumor as primary curative therapy. (Moderate Recommendation; Evidence Level: Grade C)

Primary Radiation Therapy

  1. For patients with muscle-invasive bladder cancer, clinicians should not offer radiation therapy alone as a curative treatment. (Strong Recommendation; Evidence Level: Grade C)

Multi-Modal Bladder Preserving Therapy

  1. For patients with muscle-invasive bladder cancer who have elected multi-modal bladder preserving therapy, clinicians should offer maximal transurethral resection of bladder tumor, chemotherapy combined with external beam radiation therapy, and planned cystoscopic re-evaluation. (Strong Recommendation; Evidence Level: Grade B)
  2. Radiation sensitizing chemotherapy regimens should include cisplatin or 5- fluorouracil and mitomycin C. (Strong Recommendation; Evidence Level: Grade B)
  3. Following completion of bladder preserving therapy, clinicians should perform regular surveillance with CT scans, cystoscopy, and urine cytology. (Strong Recommendation; Evidence Level: Grade C)

Bladder Preserving Treatment Failure

  1. In patients who are medically fit and have residual or recurrent muscle-invasive disease following bladder preserving therapy, clinicians should offer radical cystectomy with bilateral pelvic lymphadenectomy. (Strong Recommendation; Evidence Level: Grade C)
  2. In patients who have a non-muscle invasive recurrence after bladder preserving therapy, clinicians may offer either local measures, such as transurethral resection of bladder tumor with intravesical therapy, or radical cystectomy with bilateral pelvic lymphadenectomy. (Moderate Recommendation; Evidence Level: Grade C)

Patient Surveillance and Follow Up

Imaging

  1. Clinicians should obtain chest imaging and cross sectional imaging of the abdomen and pelvis with CT or MRI at 6-12 month intervals for 2-3 years and then may continue annually. (Expert Opinion)  

Laboratory Values and Urine Markers

  1. Following therapy for muscle-invasive bladder cancer, patients should undergo laboratory assessment at three to six month intervals for two to three years and then annually thereafter. (Expert Opinion)
  2. Following radical cystectomy in patients with a retained urethra, clinicians should monitor the urethral remnant for recurrence. (Expert Opinion)

Patient Survivorship

  1. Clinicians should discuss with patients how they are coping with their bladder cancer diagnosis and treatment and should recommend that patients consider participating in cancer support groups or consider receiving individual counseling. (Expert Opinion)
  2. Clinicians should encourage bladder cancer patients to adopt healthy lifestyle habits, including smoking cessation, exercise, and a healthy diet, to improve long-term health and quality of life. (Expert Opinion)

Variant Histology

  1. In patients diagnosed with variant histology, clinicians should consider unique clinical characteristics that may require divergence from standard evaluation and management for urothelial carcinoma. (Expert Opinion)

Introduction

Purpose

Although representing approximately 25% of patients diagnosed with bladder cancer, muscle-invasive bladder cancer (MIBC) carries a significant risk of death that has not significantly changed in decades. Increasingly, clinicians and patients recognize the importance of multidisciplinary collaborative efforts that take into account survival and quality of life (QOL) concerns. For the first time for any type of malignancy, the American Urological Association (AUA), the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO), and the Society of Urologic Oncology (SUO) have formulated a consensus, evidence-based guideline. This guideline provides a risk-stratified, clinical framework for the management of muscle-invasive urothelial bladder cancer.

Methodology

Systematic Review. The systematic review utilized to inform this guideline was conducted by a methodology team at the Pacific Northwest Evidence-based Practice Center. The original review was funded by the Agency for Healthcare Research and Quality (AHRQ),1 and a subsequent supplemental report was funded by the AUA to address additional key questions and more recently published literature. A research librarian experienced in conducting literature searches for comparative effectiveness reviews searched in Ovid MEDLINE® (January 1990 to October 2014), the Cochrane Central Register of Controlled Trials (through September 2014), the Cochrane Database of Systematic Reviews (through September 2014), Health Technology Assessments (through Third Quarter 2014), the National Health Sciences Economic Evaluation Database (through Third Quarter 2014), and the Database of Abstracts of Reviews of Effects (through Third Quarter 2014) to capture published and gray literature. The methodology team searched for unpublished studies in clinical trial registries (ClinicalTrials.gov, Current Controlled Trials, ClinicalStudyResults.org and the World Health Organization International Clinical Trials Registry Platform) and regulatory documents (Drugs@FDA.gov and FDA Medical Devices Registration and Listing). Reference lists of relevant studies and previous systematic reviews were hand-searched for additional studies. Scientific information packets were solicited from drug and device manufacturers and via a notice published in the Federal Register. Initial Database searches resulted in 3,921 potentially relevant articles. After dual review of abstracts and titles, 295 articles were selected for full-text dual review, and 39 studies (in 41 publications) were determined to meet inclusion criteria and were included in this review. A supplemental search of Ovid MEDLINE and Cochrane Central Register of Controlled Trials was conducted to capture additional published literature through February 2, 2016.

Data Extraction and Data Management. The methodology team extracted the following information into evidence tables: study design; setting; inclusion and exclusion criteria; dose and duration of treatment for experimental and control groups; duration of follow up; number of subjects screened, eligible, and enrolled; population ES-5 characteristics (including age, race/ethnicity, sex, stage of disease, and functional status); results; adverse events; withdrawals due to adverse events; and sources of funding. Methodologists verified or calculated relative risks and associated 95% confidence intervals (CIs) based on the information provided (sample sizes and incidence of outcomes in each intervention group). Methodologists noted discrepancies between calculated and reported results when present. Data extraction for each study was completed by one investigator and independently reviewed for accuracy and completeness by a second investigator.

Assessment of the Risk of Bias of Individual Studies. The methodology team assessed the risk of bias for randomized controlled trials (RCTs) and observational studies using criteria adapted from those developed by the U.S. Preventive Services Task Force.2 These criteria were applied in conjunction with the approach recommended in the AHRQ Methods Guide3 for medical interventions. Two investigators independently assessed the risk of bias of each study. Discrepancies were resolved through discussion and consensus. Each study was rated as low, medium, or high risk of bias. Methodologists rated the quality of each RCT based on the methods used for randomization, allocation concealment, and blinding; the similarity of compared groups at baseline; whether attrition was adequately reported and acceptable; similarity in use of co-interventions; compliance with allocated treatments; the use of intent-to-treat analysis; and avoidance of selective outcomes reporting.2 Methodologists rated the quality of each cohort study based on whether it enrolled a consecutive or random sample of patients meeting inclusion criteria; whether it evaluated comparable groups; whether rates of loss to follow up were reported and acceptable; whether it used accurate methods for ascertaining exposures, potential confounders, and outcomes; and whether it performed adjustment for important potential confounders (defined as a minimum of age, sex, tumor stage, and tumor grade).2 Studies rated low risk of bias were considered to have no more than very minor methodological shortcomings with their results likely to be valid. Studies rated medium risk of bias have some methodological shortcomings, but no flaw or combination of flaws judged likely to cause major bias. In some cases, the article did not report important information, making it difficult to assess its methods or potential limitations. The category of medium risk of bias is broad, and studies with this rating vary in their strengths and weaknesses; the results of some studies assessed to have medium risk of bias are likely to be valid, while others may be only possibly valid. Studies rated high risk of bias have significant flaws that may invalidate the results. They have a serious or fatal flaw or combination of flaws in design, analysis, or reporting; large amounts of missing information (including publication of only preliminary results in a subgroup of patients randomized); or serious discrepancies in reporting. Methodologists did not exclude studies rated as having high risk of bias a priori, but they were considered the least reliable when synthesizing the evidence, particularly when discrepancies between studies were present.

Determination of Evidence Strength. The categorization of evidence strength is conceptually distinct from the quality of individual studies. Evidence strength refers to the body of evidence available for a particular question and includes not only individual study quality but consideration of study design, consistency of findings across studies, adequacy of sample sizes, and generalizability of samples, settings, and treatments for the purposes of the guideline. The AUA categorizes body of evidence strength as Grade A (well-conducted and highly-generalizable RCTs or exceptionally strong observational studies with consistent findings), Grade B (RCTs with some weaknesses of procedure or generalizability or moderately strong observational studies with consistent findings), or Grade C (RCTs with serious deficiencies of procedure or generalizability or extremely small sample sizes or observational studies that are inconsistent, have small sample sizes, or have other problems that potentially confound interpretation of data). By definition, Grade A evidence is evidence about which the Panel has a high level of certainty, Grade B evidence is evidence about which the Panel has a moderate level of certainty, and Grade C evidence is evidence about which the Panel has a low level of certainty.4

AUA Nomenclature: Linking Statement Type to Evidence Strength. The AUA nomenclature system explicitly links statement type to body of evidence strength, level of certainty, magnitude of benefit or risk/burdens, and the Panel’s judgment regarding the balance between benefits and risks/burdens (Table 1). Strong Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is substantial. Moderate Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is moderate. Conditional Recommendations are non-directive statements used when the evidence indicates that there is no apparent net benefit or harm or when the balance between benefits and risks/burden is unclear. All three statement types may be supported by any body of evidence strength grade. Body of evidence strength Grade A in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances and that future research is unlikely to change confidence. Body of evidence strength Grade B in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances but that better evidence could change confidence. Body of evidence strength Grade C in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances but that better evidence is likely to change confidence. Body of evidence strength Grade C is only rarely used in support of a Strong Recommendation. Conditional Recommendations also can be supported by any evidence strength. When body of evidence strength is Grade A, the statement indicates that benefits and risks/burdens appear balanced, the best action depends on patient circumstances, and future research is unlikely to change confidence. When body of evidence strength Grade B is used, benefits and risks/burdens appear balanced, the best action also depends on individual patient circumstances and better evidence could change confidence. When body of evidence strength Grade C is used, there is uncertainty regarding the balance between benefits and risks/burdens, alternative strategies may be equally reasonable, and better evidence is likely to change confidence.

Where gaps in the evidence existed, the Panel provides guidance in the form of Clinical Principles or Expert Opinion with consensus achieved using a modified Delphi technique if differences of opinion emerged.5 A Clinical Principle is a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature. Expert Opinion refers to a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there is no evidence.

TABLE 1: AUA Nomenclature Linking Statement Type to Level of Certainty, Magnitude of Benefit or Risk/Burden, and Body of Evidence Strength

 

Evidence Strength A

(High Certainty)

Evidence Strength B

(Moderate Certainty)

Evidence Strength C

(Low Certainty)

Strong Recommendation

 

(Net benefit or harm substantial)

Benefits > Risks/Burdens (or vice versa)

Net benefit (or net harm) is substantial

Applies to most patients in most circumstances and future research is unlikely to change confidence

Benefits > Risks/Burdens (or vice versa)

Net benefit (or net harm) is substantial

Applies to most patients in most circumstances but better evidence could change confidence

 

Benefits > Risks/Burdens (or vice versa)

Net benefit (or net harm) appears substantial

Applies to most patients in most circumstances but better evidence is likely to change confidence

(rarely used to support a Strong Recommendation)

Moderate Recommendation

 

(Net benefit or harm moderate)

Benefits > Risks/Burdens (or vice versa)

Net benefit (or net harm) is moderate

Applies to most patients in most circumstances and future research is unlikely to change confidence

Benefits > Risks/Burdens (or vice versa)

Net benefit (or net harm) is moderate

Applies to most patients in most circumstances but better evidence could change confidence

Benefits > Risks/Burdens (or vice versa)

Net benefit (or net harm) appears moderate

Applies to most patients in most circumstances but better evidence is likely to change confidence

Conditional Recommendation

 

(No apparent net benefit or harm)

Benefits = Risks/Burdens

Best action depends on individual patient circumstances

Future research unlikely to change confidence

Benefits = Risks/Burdens

Best action appears to depend on individual patient circumstances

Better evidence could change confidence

Balance between Benefits & Risks/Burdens unclear

Alternative strategies may be equally reasonable

Better evidence likely to change confidence

Clinical Principle

A statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature

Expert Opinion

A statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there is no evidence

Process. The Muscle-Invasive Bladder Cancer Panel was created in 2014 by the American Urological Association Education and Research, Inc. (AUA). The Practice Guidelines Committee (PGC) of the AUA selected the Panel Chair who in turn appointed the Vice Chair. In a collaborative process, additional Panel members, including additional members of the American Society for Radiation Oncology (ASTRO), the American Society of Clinical Oncology (ASCO), and Society of Urologic Oncology (SUO), with specific expertise in this area were then nominated and approved by the PGC. The AUA conducted a thorough peer review process. The draft guideline document was distributed to 128 peer reviewers, 67 of which submitted comments. The Panel reviewed and discussed all submitted comments and revised the draft as needed. Once finalized, the guideline was submitted for approval to the PGC and Science and Quality Council (S&Q). Then it was submitted to the AUA, ASTRO, ASCO, and SUO Board of Directors for final approval. Panel members received no remuneration for their work. This represents the first joint guidelines by these organizations.

Background

Epidemiology

There are 79,030 new cases of bladder cancer and 16,870 bladder cancer deaths predicted for 2017 in the U.S.6 Approximately 25% of newly diagnosed patients have muscle-invasive disease,7,8 a rate that has not changed over the last 10 years based on data from the Surveillance, Epidemiology, and End Results (SEER) registry.9 In addition, up to 50% or more patients with high-risk non-muscle invasive bladder cancer (NMIBC) can progress to invasive disease. The male to female ratio is 3:1, and disease incidence increases with age. While rates of bladder cancer are higher in Caucasians than other ethnicities, disease specific survival is worse overall for African-Americans.6,8

Etiology

All of the factors that contribute to the development of bladder cancer are not completely understood, but exposure to carcinogens (e.g. tobacco smoke) is the primary cause with some impact from genetic susceptibility. Smoking tobacco is the most important and common risk factor and is estimated to contribute to the development of 50% of bladder tumors, with current smokers at higher risk than former smokers.10,11 Former smoking increases the risk of bladder cancer by a factor of 2.2 (95% CI 2.0-2.4), and current smoking by a factor of 4.1 (95% CI 3.7-4.5) compared to never having smoked.10 Second hand smoke can also increase the risk for the development of bladder cancer.12 Following smoking, another risk factor that predisposes to bladder cancer is occupational exposure to carcinogens, namely aromatic amines (benzidine, 4-aminobiphenyl, 2-naphthylamine, 4-chloro-o-toluidine), polycyclic aromatic hydrocarbons, and chlorinated hydrocarbons, which contribute to approximately 20% of all bladder cancers.13-15 Occupational exposure accounts for 25% of bladder cancer diagnoses in men and 11% in women.16

There are several other well-documented risk factors. Pelvic radiation for other malignancies increases the likelihood of developing bladder cancer with a hazard ratio of 1.7.17 In addition, exposure to S. haematobium infection is predominantly associated with an increased risk of squamous cell carcinoma of the bladder and is a significant clinical problem in many developing nations. This disease process is a much less common entity in the United States and not the major focus of this report.

Genetic predisposition to bladder cancer has been linked to genes involved in metabolism of carcinogens such as N-acetyl transferase and GSTM1-null genotypes.18 Large genome-wide association studies have also found sequence variants that can increase the risk for bladder cancer, such as subjects with urea transporter gene SLC14A that is associated with renal urine concentration, and thus with variations in contact of carcinogens with urothelial surfaces.19-23

Urothelial carcinoma is often multifocal with a high rate of recurrence; the exact etiology of this characteristic is currently unknown. Two of the most commonly held theories: 1) a genetic field defect exists with multiple new tumors spontaneously arising or, 2) the local reimplantation of tumor cells occurs with tumor resection. Evidence suggests that tumor reimplantation or submucosal migration may be early mechanisms for multifocality.24 Multifocal tumors as well as upper tract and lower tract lesions arising in one individual may demonstrate clonality.25

Prognosis 

The overall prognosis of patients with MIBC has not changed in the last 30 years. In patients who undergo cystectomy, systemic recurrence rates vary by stage, but range from 20-30% for pathologic stage pT2, 40% for pT3, >50% for pT4 and approximately 70% for node-positive disease.26,27 Most recurrences will occur within the first two to three years after cystectomy, and at this time, most patients with recurrence after cystectomy are not cured with current systemic therapies.28

A pooled analysis of multiple prospective Radiation Therapy Oncology Group (RTOG) protocols evaluating bladder preserving combined-modality therapy for MIBC with a median follow up of 4.3 years found the 5- and 10-year overall survival rates were 57% and 36%, respectively, and the 5- and 10-year disease specific survival rates were 71% and 65%, respectively.29

The dominant pathologic predictors for recurrence and survival are tumor stage and nodal status. Other prognostic factors include gender, presence of hydronephrosis, lymphovascular invasion, soft tissue margin status, and molecular subtyping characteristics.30-35 Variant histology has become better described and recognized, and the treatment for these cancers may vary from conventional urothelial carcinoma. There is also a significant impact of treatment choices on outcome with the type and timing of therapy playing an important role.36,37

Scope 

This evidence-based guideline for clinically non-metastatic muscle-invasive urothelial bladder cancer (cT2-T4N0M0) focuses on the evaluation, treatment, and surveillance of MIBC and is guided toward curative intent. The treatment of patients with clinically evident metastatic bladder cancer is outside the context of this guideline and will not be discussed. Optimal initial evaluation of patients with MIBC, including imaging and proper staging, are discussed. The role of radical cystectomy and bilateral pelviclymphadenectomy is defined. Bladder preserving regimens such as a multi-modal approach that combines maximal transurethral resection  of bladder tumor(TURBT), chemotherapy and radiation therapy as well as partial cystectomy, radiation alone and maximal TURBT alone, are assessed.

In addition, this guideline will discuss QOL aspects of care and the importance of careful patient counseling. The guidelines will also address timing and mode of testing used in surveillance of disease. Finally, there will be a section devoted to variant histology and the current unique aspects of care for certain non-urothelial cancers of the bladder.

Initial Patient Evaluation & Counseling

Guideline Statement 1

Prior to treatment consideration, a full history and physical exam should be performed, including an exam under anesthesia, at the time of transurethral resection of bladder tumor for a suspected invasive cancer. (Clinical Principle)

Discussion


Guideline Statement 2

Prior to muscle-invasive bladder cancer management, clinicians should perform a complete staging evaluation, including imaging of the chest and cross sectional imaging of the abdomen and pelvis with intravenous contrast if not contraindicated. Laboratory evaluation should include a comprehensive metabolic panel (complete blood count, liver function tests, alkaline phosphatase, and renal function). (Clinical Principle)

Discussion


Guideline Statement 3

An experienced genitourinary pathologist should review the pathology of a patient when variant histology is suspected or if muscle invasion is equivocal (e.g., micropapillary, nested, plasmacytoid, neuroendocrine, sarcomatoid, extensive squamous or glandular differentiation). (Clinical Principle)

Discussion


Guideline Statement 4

For patients with newly diagnosed muscle-invasive bladder cancer, curative treatment options should be discussed before determining a plan of therapy that is based on both patient comorbidity and tumor characteristics. Patient evaluation should be completed using a multidisciplinary approach. (Clinical Principle)

Discussion


Guideline Statement 5

Prior to treatment, clinicians should counsel patients regarding complications and the implications of treatment on quality of life (e.g., impact on continence, sexual function, fertility, bowel dysfunction, metabolic problems). (Clinical Principle)

Discussion


Treatment

Neoadjuvant/Adjuvant Chemotherapy

Guideline Statement 6

Utilizing a multidisciplinary approach, clinicians should offer cisplatin-based neoadjuvant chemotherapy to eligible radical cystectomy patients prior to cystectomy. (Strong Recommendation; Evidence Level: Grade B)

Discussion


Guideline Statement 7

Clinicians should not prescribe carboplatin-based neoadjuvant chemotherapy for clinically resectable stage cT2-T4aN0 bladder cancer. Patients ineligible for cisplatin-based neoadjuvant chemotherapy should proceed to definitive locoregional therapy. (Expert Opinion)

Discussion


Guideline Statement 8

Clinicians should perform radical cystectomy as soon as possible following a patient’s completion of and recovery from neoadjuvant chemotherapy. (Expert Opinion)

Discussion


Guideline Statement 9

Eligible patients who have not received cisplatin-based neoadjuvant chemotherapy and have non-organ confined (pT3/T4and/or N+) disease at cystectomy should be offered adjuvant cisplatin- based chemotherapy. (Moderate Recommendation; Evidence Level: Grade C)

Discussion


Radical Cystectomy

Guideline Statement 10

Clinicians should offer radical cystectomy with bilateral pelvic lymphadenectomy for surgically eligible patients with resectable non-metastatic (M0) muscle-invasive bladder cancer. (Strong Recommendation; Evidence Level: Grade B)

Discussion


Guideline Statement 11

When performing a standard radical cystectomy, clinicians should remove the bladder, prostate, and seminal vesicles in males and should remove the bladder, uterus, fallopian tubes, ovaries, and anterior vaginal wall in females.  (Clinical Principle)

Discussion


Guideline Statement 12

Clinicians should discuss and consider sexual function preserving procedures for patients with organ-confined disease and absence of bladder neck, urethra, and prostate (male) involvement. (Moderate Recommendation; Evidence Level: Grade C)

Discussion


Urinary Diversion

Guideline Statement 13

In patients undergoing radical cystectomy, ileal conduit, continent cutaneous, and orthotopic neobladder urinary diversions should all be discussed. (Clinical Principle)

Discussion


Guideline Statement 14

In patients receiving an orthotopic urinary diversion, clinicians must verify a negative urethral margin. (Clinical Principle)

Discussion


Perioperative Surgical Management

Guideline Statement 15

Clinicians should attempt to optimize patient performance status in the perioperative setting. (Expert Opinion)

Discussion


Guideline Statement 16

Perioperative pharmacologic thromboembolic prophylaxis should be given to patients undergoing radical cystectomy. (Strong Recommendation; Evidence Level: Grade B)

Discussion


Guideline Statement 17

In patients undergoing radical cystectomy µ -opioid antagonist therapy should be used to accelerate gastrointestinal recovery, unless contraindicated. (Strong Recommendation; Evidence Level: Grade B)

Discussion


Guideline Statement 18

Patients should receive detailed teaching regarding care of urinary diversion prior to discharge from the hospital. (Clinical Principle)

Discussion


Pelvic Lymphadenectomy

Guideline Statement 19

Clinicians must perform a bilateral pelvic lymphadenectomy at the time of any surgery with curative intent. (Strong Recommendation; Evidence Level: Grade B)

Discussion


Guideline Statement 20

When performing bilateral pelvic lymphadenectomy, clinicians should remove, at a minimum, the external and internal iliac and obturator lymph nodes (standard lymphadenectomy). (Clinical Principle)

Discussion


Bladder Preserving Approaches

Patient Selection

A multi-modal bladder preserving approach with its merits and disadvantages should be discussed in each individual case. The studies that support bladder preserving strategies, as a general rule, have highly select patient populations. There are currently no randomized trials comparing NAC and radical cystectomy versus multi-modality bladder preserving therapies. In reviewing the available studies regarding multi-modal bladder preserving protocols that employ TURBT, radiation therapy, and chemotherapy for carefully selected patients, the Panel found no strong evidence to determine whether or not immediate cystectomy improved survival when compared to initial bladder sparing protocols that employ salvage cystectomy as therapy for persistent bladder cancer.123-131 In addition, no high quality evidence directly compares QOL between the different treatment options; instead a number of studies report on health-related QOL outcomes and draw comparisons to other therapies. The Panel also recognizes that other non-multi-modal bladder–preserving regimens, although having less oncologic efficacy as well as less data, do exist and may be a reasonable option for certain patients, especially those who have poorer performance status.

Guideline Statement 21

For patients with newly diagnosed non-metastatic muscle-invasive bladder cancer who desire to retain their bladder, and for those with significant comorbidities for whom radical cystectomy is not a treatment option, clinicians should offer bladder preserving therapy when clinically appropriate. (Clinical Principle)

Discussion


Guideline Statement 22

In patients under consideration for bladder preserving therapy, maximal debulking transurethral resection of bladder tumor and assessment of multifocal disease/carcinoma in situ should be performed. (Strong Recommendation; Evidence Level: Grade C)

Discussion


Maximal TURBT and Partial Cystectomy

Guideline Statement 23

Patients with muscle-invasive bladder cancer who are medically fit and consent to radical cystectomy should not undergo partial cystectomy or maximal transurethral resection of bladder tumor as primary curative therapy. (Moderate Recommendation; Evidence Level: Grade C)

Discussion


Primary Radiation Therapy

Guideline Statement 24

For patients with muscle-invasive bladder cancer, clinicians should not offer radiation therapy alone as a curative treatment. (Strong Recommendation; Evidence Level: Grade C)

Discussion


Multi-Modal Bladder Preserving Therapy

Guideline Statement 25

For patients with muscle-invasive bladder cancer who have elected multi-modal bladder preserving therapy, clinicians should offer maximal transurethral resection of bladder tumor, chemotherapy combined with external beam radiation therapy, and planned cystoscopic re-evaluation. (Strong Recommendation; Evidence Level: Grade B)

Discussion


Guideline Statement 26

Radiation sensitizing chemotherapy regimens should include cisplatin or 5- fluorouracil and mitomycin C. (Strong Recommendation; Evidence Level: Grade B)

Discussion


Guideline Statement 27

Following completion of bladder preserving therapy, clinicians should perform regular surveillance with CT scans, cystoscopy, and urine cytology. (Strong Recommendation; Evidence Level: Grade C)

Discussion


Bladder Preserving Treatment Failure

Guideline Statement 28

In patients who are medically fit and have residual or recurrent muscle-invasive disease following bladder preserving therapy, clinicians should offer radical cystectomy with bilateral pelvic lymphadenectomy. (Strong Recommendation; Evidence Level: Grade C)

Discussion


Guideline Statement 29

In patients who have a non-muscle invasive recurrence after bladder preserving therapy, clinicians may offer either local measures, such as transurethral resection of bladder tumor with intravesical therapy, or radical cystectomy with bilateral pelvic lymphadenectomy. (Moderate Recommendation; Evidence Level: Grade C)

Discussion


Patient Surveillance & Follow Up

Imaging

Guideline Statement 30

Clinicians should obtain chest imaging and cross sectional imaging of the abdomen and pelvis with CT or MRI at 6-12 month intervals for 2-3 years and then may continue annually. (Expert Opinion)  

Discussion


Laboratory Values and Urine Markers

Guideline Statement 31

Following therapy for muscle-invasive bladder cancer, patients should undergo laboratory assessment at three to six month intervals for two to three years and then annually thereafter. (Expert Opinion)

Discussion


Guideline Statement 32

Following radical cystectomy in patients with a retained urethra, clinicians should monitor the urethral remnant for recurrence. (Expert Opinion)

Discussion


Patient Survivorship

Guideline Statement 33

Clinicians should discuss with patients how they are coping with their bladder cancer diagnosis and treatment and should recommend that patients consider participating in a cancer support group or consider receiving individual counseling. (Expert Opinion)

Discussion


Guideline Statement 34

Clinicians should encourage bladder cancer patients to adopt healthy lifestyle habits, including smoking cessation, exercise, and a healthy diet, to improve long-term health and quality of life. (Expert Opinion)

Discussion


Variant Histology

Guideline Statement 35

In patients diagnosed with variant histology, clinicians should consider unique clinical characteristics that may require divergence from standard evaluation and management for urothelial carcinoma. (Expert Opinion)

Discussion


Future Research

Several key areas of future research need emphasis to improve clinical care and provide a path to better patient outcomes with invasive bladder cancer.

Detection and markers. Enhanced detection of bladder cancer cells via imaging technology or other means is needed to identify patients with high-risk disease and advanced disease.  This includes cystocopic and radiographic imaging of local disease and more effective and accurate evaluation techniques of regional lymphatics and distant sites.  Defining the role of PET imaging and the best PET imaging agent as well as the investigation and validation of other novel technologies are deemed high-priority.

Urine cytology can be used to monitor for recurrence after TURBT and cystectomy, but difficulties with interpretation after urinary diversion have limited its usefulness after bladder removal. Radiation therapy can alter the appearance of shed cells and oftentimes result in atypical results. Current urinary markers have a limited role in the routine monitoring for recurrence of urothelial carcinoma after radical cystectomy due to false positive rate. Future studies should focus on the development of urinary and serum based markers that can be used to identify early urothelial based and/or distant recurrences.

Increased knowledge gained from comprehensive genetic studies of invasive bladder cancer should be exploited to identify and validate markers that could be used to guide diagnosis and therapeutic decision making. This would include the identification of prognostic markers capable of stratifying patients at risk for advanced disease, predictive markers for the response to chemotherapeutic/immunotherapeutic agents as well as radiation-based therapies.  In addition, further studies are needed to evaluate and validate the prognostic and predictive information obtained from novel molecular classifications of bladder cancer.

Therapy. The rapid introduction of novel immunotherapeutic agents into the therapeutic armamentarium for treatment of bladder cancer has begun to show promise. Phase II and III studies have now demonstrated significant antitumor activity of the anti-PD-1 and anti-PDL-1 antibodies in the metastatic setting.  A myriad of studies are needed to further define the role of these agents alone or in combination with other therapies for all stages of bladder cancer.

In addition, further studies are needed to better integrate multi-modal therapy in patients with invasive bladder cancer. Specific examples include the role for AC or immunotherapy in patients who have previously received NAC followed by surgery but still possess high-risk pathology (residual invasive disease or regional lymph node involvement); and the role of radiation in patients undergoing radical cystectomy for T3 and T4 disease, including the use of intraoperative radiation therapy.

In terms of surgery, robotic technology has entered into the treatment of patients with invasive bladder cancer with the hope that it will improve the morbidity associated with radical cystectomy.  Long-term data is needed to demonstrate the oncologic efficacy, potential for improved clinical outcomes, and QOL using this new technology compared to standard open techniques. RCTs currently underway may give additional information regarding the utility of robotic surgery in MIBC. (NCT01157676)

Pelvic lymphadenectomy is an important part of a radical cystectomy, improving control of local/regional disease and providing better long-term outcomes. The exact extent of the lymphadenectomy still has yet to be defined.  Current properly powered long-term surgical trial results will help define the incremental benefit of an “extended” lymphadenectomy compared to a “standard” lymphadenectomy. (NCT01224665 and LEA AUO AB 25/02)

Tissue regenerative technology continues to advance, stimulating the hope that organ replacement may be available in the future.  Support of basic and translational research is needed to move tissue regeneration forward into clinical use for patients who require bladder removal for invasive bladder cancer.

In addition, studies emphasizing PROs after treatment for invasive bladder cancer are needed. This information is necessary to help further support patient centered outcomes, and identify specific areas of treatment that require further attention to improve patient QOL.

Surveillance. Finally, the optimal strategies for surveillance after definitive treatment for invasive bladder cancer to identify pelvic, distant, and urothelial recurrences need to be defined. Specifically, the role of specific imaging tests and laboratory studies as well as their appropriate interval has yet to be established, and future studies are needed to define a patient specific approach.

Tools and Resources

For Patients

References

1. Chou R, Selph S, Buckley D, Gustafson K, Griffin J, Grusing S, Gore J. Treatment of Nonmetastatic Muscle-Invasive Bladder Cancer. Comparative Effectiveness Review No. 152. (Prepared by the Pacific Northwest Evidence-based Practice Center under Contract No. 290-2012-00014-1.) AHRQ Publication No. 15-EHC015-EF. Rockville, MD: Agency for Healthcare Research and Quality; June 2015.

2. U.S. Preventive Services Task Force. U.S. Preventive Services Task Force Procedure Manual. 2008. www.uspreventiveservicestaskforce.org/usp stf08/methods/procmanual.htm. Accessed April 4, 2014.

3. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 10(14)-EHC063-EF. Rockville, MD: Agency for Healthcare Research and Quality. January 2014. Chapters available at www.effectivehealthcare.ahrq.gov.

4. Faraday M, Hubbard H, Kosiak B et al: Staying at the cutting edge: a review and analysis of evidence reporting and grading; the recommendations of the American Urological Association. BJU Int 2009; 104: 294.

5. Hsu C and Sandford BA: The Delphi technique: making sense of consensus. Practical Assessment, Research & Evaluation 2007; 12: 1.

6. Siegel RL, Miller KD and Jemal A: Cancer statistics, 2017. CA Cancer J Clin 2016; 67: 7.

7. Smith AB, Deal AM, Woods ME et al: Muscle-invasive bladder cancer: evaluating treatment and survival in the National Cancer Data Base. BJU Int 2014; 114: 719.

8. Burger M, Catto JW, Dalbagni G et al: Epidemiology and risk factors of urothelial bladder cancer. Eur Urol 2013; 63:234.

9. Charlton ME, Adamo MP, Sun L et al: Bladder cancer collaborative stage variables and their data quality, usage, and clinical implications: a review of SEER data, 2004-2010. Cancer 2014; 120 3815.

10. Freedman ND, Silverman DT, Hollenbeck AR et al: Association between smoking and risk of bladder cancer among men and women. JAMA 2011; 306:737.

11. Samanic C, Kogevinas M, Dosemeci M et al: Smoking and bladder cancer in Spain: effects of tobacco type, timing, environmental tobacco smoke, and gender. Cancer Epidemiol Biomarkers Prev 2006; 15: 1348.

12. Jiang X, Yuan JM, Skipper PL et al: Environmental tobacco smoke and bladder cancer risk in never smokers of Los Angeles County. Cancer Res 2007; 67: 7540.

13. Rushton L, Bagga S, Bevan R et al: Occupation and cancer in Britain. Br J Cancer 2010; 102: 1428.

14. Samanic CM, Kogevinas M, Silverman DT et al: Occupation and bladder cancer in a hospital-based case-control study in Spain. Occup Environ Med 2008; 65: 347.

15. Koutros S, Silverman DT, Baris D et al: Hair dye use and risk of bladder cancer in the New England bladder cancer study. Int J Cancer 2011; 129: 2894.

16. Van der Poel HG, Mungan NA and Witjes JA: Bladder cancer in women. Int Urogynecol J and pelvic floor dysfunction 1999; 10: 207.

17. Abern MR, Dude AM, Tsivian M et al:The characteristics of bladder cancer after radiotherapy for prostate cancer. Urol Oncol 2013; 31:1628.

18. An Y, Li H, Wang KJ et al: Meta-analysis of the relationship between slow acetylation of N-acetyl transferase 2 and the risk of bladder cancer. Genet Mol Res 2015; 14: 16896.

19. Guey LT, García-Closas M, Murta-Nascimento C et al: EPICURO/Spanish Bladder Cancer Study investigators. Genetic susceptibility to distinct bladder cancer subphenotypes. Eur Urol 2010; 57: 283.

20. Kiemeney LA, Sulem P, Besenbacher S et al: A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer. Nat Genet 2010; 42:415.

21. Kiemeney LA, Thorlacius S, Sulem P et al: Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nat Genet 2008; 40: 1307.

22. Wu X, Ye Y, Kiemeney LA et al: A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat Genet 2009; 41: 991.

23. Rothman N, Garcia-Closas M, Chatterjee N et al: A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat Genet 2010; 42:978.

24. Bryan RT, Collins SI, Daykin MC et al: Mechanisms of recurrence of Ta/T1 bladder cancer. Ann R Coll Surg Engl 2010; 92: 519.

25. Lamy P, Nordentoft I, Birkenkamp-Demtröder K et al: Paired exome analysis reveals clonal evolution and potential therapeutic targets in urothelial carcinoma.Cancer Res 2016; 76: 5894.

26. Karakiewicz PI, Shariat SF, Palapattu GS et al: Nomogram for predicting disease recurrence after radical cystectomy for transitional cell carcinoma of the bladder. J Urol 2006; 176: 1354.

27. International Bladder Cancer Nomogram Consortium, Bochner BH, Kattan MW et al: Postoperative nomogram predicting risk of recurrence after radical cystectomy for bladder cancer. J Clin Oncol 2006; 24: 3967.

28 Seisen T, Sun M, Leow JJ et al: Efficacy of high-intensity local treatment for metastatic urothelial carcinoma of the bladder: a propensity score-weighted analysis from the National Cancer Data Base. J Clin Oncol 2016; Epub ahead of print.

29. Mak RH, Hunt D, Shipley WU et al: Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233 J Clin Oncol 2014; 32:3801.

30. Dobruch J, Daneshmand S, Fisch M et al: Gender and bladder cancer: a collaborative review of etiology, biology, and outcomes. Eur Urol 2016; 69: 300.

31. Lotan Y, Gupta A, Shariat SF et al: Lymphovascular invasion is independently associated with overall survival, cause-specific survival, and local and distant recurrence in patients with negative lymph nodes at radical cystectomy. J Clin Oncol 2005; 23:6533.

32. Choi W, Czerniak B, Ochoa A et al: Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer. Nat Rev Urol 2014; 11: 400.

33. Xylinas E, Rink M, Novara G et al: Predictors of survival in patients with soft tissue surgical margin involvement at radical cystectomy. Ann Surg Oncol 2013; 20:1027.

34. Cancer Genome Atlas Research Network: Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 2014; 507: 315.

35. Sjodahl G, Lauss M, Lovgren K et al: A molecular taxonomy for urothelial carcinoma. Clin Cancer Res 2012; 18: 3377.

36. Choi W, Porten S, Kim S et al: Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 2014; 25: 152.

37. Damrauer JS, Hoadley KA, Chism DD et al: Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci USA 2014; 111 3110.

38. Koppie TM, Serio AM, Vickers AJ et al: Age-adjusted Charlson comorbidity score is associated with treatment decisions and clinical outcomes for patients undergoing radical cystectomy for bladder cancer. Cancer 2008; 112:2384.

39. Lotan Y, Amiel G, Boorjian SA et al: Comprehensive handbook for developing a bladder cancer cystectomy database. Bladder Cancer Think Tank; Bladder Cancer Advocacy Network.

40. Marshall, VF: The relation of the preoperative estimate to the pathologic demonstration of the extent of vesicle neoplasms. J Urol 1952; 68:714.

41. Culp SH, Dickstein RJ, Grossman HB et al:Refining patient selection for neoadjuvant chemotherapy before radical cystectomy. J Urol 2014; 191:40.

42. Husband JE, Olliff JF, Williams MP et al: Bladder cancer: staging with CT and MR imaging. Radiology 1989; 173: 435.


43. Vargas HA, Akin O, Schoder H et al: Prospective evaluation of MRI, 11.C- acetate PET/CT and contrast-enhanced CT for staging of bladder cancer. Eur J Radiol 2012; 81: 4131.

44. Moyer VA; U.S. Preventive Services Task Force: Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014; 160:330.

45. Braendengen M, Winderen M and Fosså SD: Clinical significance of routine pre-cystectomy bone scans in patients with muscle-invasive bladder cancer. Br J Urol 1996; 77: 36.

46. Aljabery F, Lindblom G, Skoog S et al: PET/CT versus conventional CT for detection of lymph node metastases in patients with locally advanced bladder cancer. BMC Urol 2015; 15: 87.

47. Jeong IG, Hong S, You D et al: FDG PET-CT for lymph node staging of bladder cancer: a prospective study of patients with extended pelvic lymphadenectomy. Ann Surg Oncol 2015; 22: 3150.

48. Kibel AS, Dehdashti F, Katz MD et al: Prospective study of 18Ffluorodeoxyglucose positron emission tomography/computed tomography for staging of muscle-invasive bladder carcinoma. J Clin Oncol 2009; 27: 4314.

49. Sangoi AR, Beck AH, Amin MB et al: Interobserver reproducibility in the diagnosis of invasive micropapillary carcinoma of the urinary tract among urologic pathologists.Am J Surg Pathol 2010; 34: 1367.

50. Linder BJ, Boorjian SA, Cheville JC et al: The impact of histological reclassification during pathology re-review-- evidence of a Will Rogers effect in bladder cancer? J Urol 2013; 190: 1692.

51. Hansel DE, Amin MB, Comperat E et al: A contemporary update on pathology standards for bladder cancer: transurethral resection and radical cystectomy specimens. Eur Urol 2013; 63: 321.

52. Kim SP, Frank I, Cheville JC et al: The impact of squamous and glandular differentiation on survival after radical cystectomy for urothelial carcinoma. J Urol 2012; 188: 405.

53. Linder BJ, Frank I, Cheville JC et al: Outcomes following radical cystectomy for nested variant of urothelial carcinoma: a matched cohort analysis. J Urol 2013; 189: 1670.

54. Wang JK, Boorjian SA, Cheville JC et al: Outcomes following radical cystectomy for micropapillary bladder cancer versus pure urothelial carcinoma: a matched cohort analysis. World J Urol 2012; 30: 801.

55. Kassouf W, Spiess PE, et al: Prostatic urethral biopsy has limited usefulness in counseling patients regarding final urethral margin status during orthotopic neobladder reconstruction J Urol 2008; 180: 164.

56. Psutka SP, Carrasco A, Schmit GD et al: Sarcopenia in patients with bladder cancer undergoing radical cystectomy: impact on cancer-specific and all-cause mortality.Cancer 2014; 120: 2910.

57. Carli F, Awasthi R, Gillis C et al: Optimizing a frail elderly patient for radical cystectomy with a prehabilitation program. Can Urol Assoc J 2014; 8:E884.

58. Chhabra KR, Sacks GD and Dimick JB: Surgical decision making: challenging dogma and incorporating patient preferences. JAMA 2017; 317: 357.

59. Bladder Cancer: EORTC QLQ-NMIBC24, EORTC QLQBLM30 Internet. Available from: http://groups.eortc.be/qol/bladder-cancer-eortc-qlq-nmibc24-eortc-qlq-blm30.

60. Blazeby JM, Hall E, Aaronson NK et al: Validation and reliability testing of the EORTC QLQ-NMIBC24 questionnaire module to assess patient-reported outcomes in non0muscle invasive bladder cancer. Eur Urol 2014; 66: 1148.

61. Anderson CB, Feurer ID, Large MC et al: Psychmetric characteristics of a condition-specific, health-related quality-of-life survey: the FACT-Vanderbilt Cystectomy Index. Urology 2012; 80: 77.

62. Gilbert SM, Dunn RL, Hollenbeck BK et al: Development and validation of the Bladder Cancer Index: a comprehensive, disease specific measure of health related quality of life in patients with localized bladder cancer. J Urol 2010; 183: 1764.

63. Danna BJ, Metcalfe MJ, Wood EL et al: Assessing symptom burden in bladder cancer: an overview of bladder cancer specific health-related quality of life instruments. Bladder Cancer 2016; 2: 329.

64. Siegrist T, Savage C, Shabsigh A et al: Analysis of gender differences in early perioperative complications following radical cystectomy at a tertiary cancer center using a standardized reporting methodology. Urol Oncol 2010; 28: 112.

65. Froehner M, Brausi MA, Herr HW et al: Complications following radical cystectomy for bladder cancer in the elderly. Eur Urol 2009; 56: 443.

66. Quek ML, Stein JP, Daneshmand S et al: A critical analysis of perioperative mortality from radical cystectomy. J Urol 2006; 175:886.

67. Novara G, Catto JW, Wilson T et al: Systematic review and cumulative analysis of perioperative outcomes and complications after robot-assisted radical cystectomy. Eur Urol 2015; 67: 376.

68. Bream MJ, Maurice MJ, Altschuler J et al: Increased use of cystectomy in patients 75 and older: a contemporary analysis of survival and perioperative outcomes from the National Cancer Database. Urology 2017; 100: 72.

69. Djaladat H, Katebian B, Bazargani ST .et al: 90-Day complication rate in patients undergoing radical cystectomy with enhanced recovery protocol: a prospective cohort study. World J Urol 2016; Epub ahead of print.

70. Chappidi MR, Kates M, Stimson CJ et al: Causes, timing, hospital costs and perioperative outcomes of index vs nonindex hospital readmissions after radical cystectomy: implications for regionalization of care. J Urol 2017; 197: 296.

71. Hu M, Jacobs BL, Montgomery JS et al: Sharpening the focus on causes and timing of readmission after radical cystectomy for bladder cancer. Cancer 2014; 120: 1409.

72. Bochner BH, Dalbagni G, Sjoberg DD et al: Comparing open radical cystectomy and robot-assisted laparoscopic radical cystectomy: a randomized clinical trial. Eur Urol 2015; 67: 1042.

73. Murthy V, Masodkar R, Kalyani N et al: Clinical outcomes with dose-escalated adaptive radiation therapy for urinary bladder cancer: a prospective study. Int J Radiat Oncol Biol Phys 2016; 94:60.

74. Zietman AL, Sacco D, Skowronski U et al: Organ conservation in invasive bladder cancer by transurethral resection, chemotherapy and radiation: results of a urodynamic and quality of life study on long-term survivors. J Urol 2003; 170: 1772.

75. Lee RK, Abol-Enein H, Artibani W et al:Urinary diversion after radical cystectomy for bladder cancer: options, patient selection, and outcomes. BJU Int 2014; 113:11.

76. Gross T, Meierhans Ruf SD, Meissner C .et al: Orthotopic ileal bladder substitution in women: factors influencing urinary incontinence and hypercontinence. Eur Urol 2015; 68: 664.

77. Hautmann RE, de Petriconi RC and Volkmer BG: Lessons learned from 1,000 neobladders: the 90-day complication rate. J Urol 2010; 184: 990.

78. Studer UE, Burkhard FC, Schumacher M et al: Twenty years experience with an ileal orthotopic low pressure bladder substitute--lessons to be learned. J Urol 2006;176: 161.

79. Ali-el-Dein B, Shaaban AA, Abu-Eideh RH et al: Surgical complications following radical cystectomy and orthotopic neobladders in women. J Urol 2008; 180: 206.

80. Ahmadi H, Skinner EC, Simma-Chiang V et al: Urinary Functional Outcome Following Radical Cystoprostatectomy and Ileal Neobladder Reconstruction in Male Patients. J Urol 2013; 189:1782.

81. Hautmann RE, Paiss T and de Petriconi R: The ileal neobladder in women: 9 years of experience with 18 patients. J Urol 1996; 155: 76.

82. Hautmann RE, de Petriconi R, Kleinschmidt K et al: Orthotopic ileal neobladder in females: impact of the urethral resection line on functional results. Int Urogynecol J Pelvic Floor Dysfunct 2000; 11:224.

83. Stein JP, Ginsberg DA and Skinner DG: Indications and technique of the orthotopic neobladder in women. Urol Clin North Am 2002; 29: 725.

84. Bartsch G, Daneshmand S, Skinner EC et al: Urinary functional outcomes in female neobladder patients. World J Urol 2014; 32: 221.

85. Colombo R, Pellucchi F, Moschini M et al:Fifteen-year single-centre experience with three different surgical procedures of nerve-sparing cystectomy in selected organ-confined bladder cancer patients. World J Urol 2015; 33:1389.

86. Zahran MH, Fahmy O, El-Hefnawy AS et al: Female sexual dysfunction post radical cystectomy and urinary diversion. Climacteric 2016; 20:1.

87. Feuerstein MA and Goenka A: Quality of life outcomes for bladder cancer patients undergoing bladder preservation with radiotherapy. Curr Urol Rep 2015; 16:75.

88. Eisenberg MS, Thompson RH, Frank I et al: Long-term renal function outcomes after radical cystectomy. J Urol 2014; 191: 619.

89. Gupta A, Atoria CL, Ehdaie B et al: Risk of fracture after radical cystectomy and urinary diversion for bladder cancer. J Clin Oncol 2014 ;32: 3291.

90. International Collaboration of Trialists: Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. Lancet 1999; 354:533.

91. International Collaboration of Trialists, Medical Research Council Advanced Bladder Cancer Working Party, European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group et al: International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol 2011; 29: 2171.

92. Grossman HB, Natale RB, Tangen CM et al: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003; 349:859.

93. Malmstrom PU, Rintala E, Wahlqvist R et al: Five-year follow-up of a prospective trial of radical cystectomy and neoadjuvant chemotherapy: Nordic Cystectomy Trial I. The Nordic Cooperative Bladder Cancer Study Group. J Urol 1996; 155: 1903.

94. Rintala E, Hannisdahl E, Fossa SD et al: Neoadjuvant chemotherapy in bladder cancer: a randomized study. Nordic Cystectomy Trial I. Scand J Urol Nephrol 1993; 27:355.

95. Sengelov L, von der Maase H, Lundbeck F et al: Neoadjuvant chemotherapy with cisplatin and methotrexate in patients with muscle-invasive bladder tumours. Acta Oncologica. 2002; 41: 447.

96. Sherif A, Rintala E, Mestad O et al: Neoadjuvant cisplatin-methotrexate chemotherapy for invasive bladder cancer -- Nordic cystectomy trial 2. Scand J Urol Nephrol 2002; 36: 419.

97. Plimack ER, Hoffman-Censits JH, Viterbo R et al: Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity. J Clin Oncol 2014; 32: 1895.

98. Choueiri TK, Jacobus S, Bellmunt J et al: Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol 2014; 32: 1889.

99. Bamias A, Dafni U, Karadimou A et al: Prospective, open-label, randomized, phase III study of  two dose-dense regimens MVAC versus gemcitabine/cisplatin in patients with inoperable, metastatic or relapsed urothelial cancer: a Hellenic Cooperative Oncology Group study (HE 16/03). Ann Oncol 2013; 24: 1011.

100. Sternberg CN, de Mulder P, Schornagel JH et al: Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer 2006; 42: 50.

101. Sternberg CN, de Mulder P, Schornagel JH et al: Randomized phase III trial of high-dose intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MCAV) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol 2001; 19: 2638.

102. Stadler WM, Lerner SP, Groshen S et al: Phase III study of molecularly targeted adjuvant therapy in locally advanced urothelial cancer of the bladder based on p53 status. J Clin Oncol 2011; 29: 3443.

103. Van Allen EM, Mouw KW, Kim P et al: Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov 2014; 4: 1140.

104. Lee JK, Havaleshko DM, Cho H et al: A strategy for predicting the chemosensitivity of human cancers and its application to drug discover. Proc Natl Acad Sci USA 2007; 104: 13086.

105. Plimack ER, Dunbrack RL, Brennan TA et al:Defects in DNA repair predict response to neoadjuvant cisplatin-based chemotherapy in muscle-invasive bladder cancer. Eur Urol 2015; 68: 959.

106. Fairey AS, Daneshmand S, Quinn D et al: Neoadjuvant chemotherapy with gemcitabine/cisplatin vs. methotrexate/vinblastine/doxorubicin/cisplatin for muscle-invasive urothelial carcinoma of the bladder: a retrospective analysis from the University of Southern California. Urol Oncol 2013; 31: 1737.

107. Pal SK, Ruel NH, Wilson TG et al: Retrospective analysis of clinical outcomes with neoadjuvant cisplatin-based regimens for muscle-invasive bladder cancer. Clin Genitourin Cancer 2012; 10:246.

108. Yeshchina O, Badalato GM, Wosnitzer MS et al: Relative efficacy of perioperative gemcitabine and cisplatin versus methotrexate, vinblastine, adriamycin, and cisplatin in the management of locally advanced urothelial carcinoma of the bladder. Urology 2012; 79:384.

109. Galsky MD, Pal SK, Chowdhury S et al: Comparative effectiveness of gemcitabine plus cisplatin versus methotrexate, vinblastine, doxorubicin, plus cisplatin as neoadjuvant therapy for musle-invasive bladder cancer. Cancer 2015; 121: 2586.

110. Galsky MD, Hahn NM, Rosenberg J et al: A consensus definition of patients with metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy. Lancet Oncol 2011; 12211.

111. Koie T, Ohyama C, Yamamoto H et al: Neoadjuvant gemcitabine and carboplatin followed by immediate cystectomy may be associated with a survival benefit in patients with clinical T2 bladder cancer. Med Oncol 2014; 31: 949.

112. Dogliotti L, Carteni G, Siena S et al: Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol 2007; 52: 134.

113. Dreicer R, Manola J, Roth BJ et al: Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer 2004; 100: 1639.

114. Alva AS, Tallman CT, He C et al: Efficient delivery of radical cystectomy after neoadjuvant chemotherapy for muscle-invasive bladder cancer. Cancer 2012; 118: 44.

115. Freiha F, Reese J, Torti FM: A randomized trial of radical cystectomy versus radical cystectomy plus cisplatin, vinblastine and methotrexate chemotherapy for muscle invasive bladder cancer. J Urol 1996; 155:495.

116. Cognetti F, Ruggeri EM, Felici A et al: Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian, multicenter, randomized phase III trial. Ann Oncol 2012; 23:695.

117. Skinner DG, Daniels JR, Russell CA et al: The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. J Urol 1991;145:459.

118. Bono AV, Benvenuti C, Gibba A et al: Adjuvant chemotherapy in locally advanced bladder cancer. Final analysis of a controlled multicentre study. Acta Urologica Italica 1997; 11:5.

119. Sternberg CN, Skoneczna I, Kerst JM et al: Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol 2015; 16: 76.

120. Leow JJ, Martin-Doyle W, Rajagopal PS et al: Adjuvant chemotherapy for invasive bladder cancer: a 2013 updated systematic review and meta-analysis of randomized trials. Eur Urol 2014; 66: 42.

121. Advanced Bladder Cancer (ABC) Meta-analysis Collaboration: Adjuvant chemotherapy for invasive bladder cancer (individual patient data). Cochrane Database Syst Rev 2006; 19: CD06018.

122. Stenzl A, Witjes JA and Comperat E: Guidelines on bladder cancer muscle-invasive and metastatic. EAU 2012.

123. Sell A, Jakobsen A, Nerstrom,B et al: Treatment of advanced bladder cancer category T2 T3 and T4a. A randomized multicenter study of preoperative irradiation and cystectomy versus radical irradiation and early salvage cystectomy for residual tumor. DAVECA protocol 8201. Danish Vesical Cancer Group. Scand J Urol Nephrol Suppl 1991; 138: 193.

124. Bekelman JE, Handorf EA, Guzzo T et al: Radical cystectomy versus bladder-preserving therapy for muscle-invasive urothelial carcinoma: examining confounding and misclassification biasin cancer observational comparative effectiveness research. Value Health 2013; 16: 610.

125. Goossens-Laan CA, Leliveld AM, Verhoeven RHA et al: Effects of age and comorbidity on treatment and survival of patients with muscle-invasive bladder cancer. Int J Cancer 2014; 135: 905.

126. Holmang S, Hedelin H, Anderstrom C et al: Long-term follow-up of all patients with muscle invasive (stages T2, T3 and T4) bladder carcinoma in a geographical region. J Urol 1997; 158: 389.

127. Kalogeras D, Lampri E, Goussia A et al: Radical therapy for muscle-infiltrating bladder cancer (cystectomy or radiotherapy): does age affect the final therapeutic benefit for the patient? J BUON 2008; 13: 353.

128. Kotwal S, Choudhury A, Johnston C et al: Similar treatment outcomes for radical cystectomy and radical radiotherapy in invasive bladder cancer treated at a United Kingdom specialist treatment center. Int J Radiat Oncol Biol Phys 2008; 70: 456.

129. Nieuwenhuijzen JA, Pos F, Moonen LMF et al: Survival after bladder-preservation with brachytherapy versus radical cystectomy; a single institution experience. Eur Urol, 2005; 48: 239.

130. Rincon Mayans A, Rosell Costa D, Zudaire Bergera JJ et al: Response and progression-free survival in T2 to T4 bladder tumors treated with trimodality therapy with bladder preservation. Actas Urol Esp 2010;34:775.

131. Solsona E, Climent MA, Iborra I et al: Bladder preservation in selected patients with muscle-invasive bladder cancer by complete transurethral resection of the bladder plus systemic chemotherapy: long-term follow-up of a phase 2 nonrandomized comparative trial with radical cystectomy. Eur Urol 2009; 55: 911.

132. Parekh DJ, Messer J, Fitzgerald J et al: Perioperative outcomes and oncologic efficacy from a pilot prospective randomized clinical trial of open versus robotic assisted radical cystectomy. J Urol 2013; 189: 474.

133. Messer JC, Punnen S, Fitzgerald J et al: Health-related quality of life from a prospective randomised clinical trial of robot-assisted laparoscopic vs open radical cystectomy. BJU Int 2014;114: 896.

134. Nix J, Smith A, Kurpad R et al: Prospective randomized controlled trial of robotic versus open radical cystectomy for bladder cancer: perioperative and pathologic results. Eur Urol 2010; 57: 196.

135. Yuh B, Wilson T, Bochner B et al: Systematic review and cumulative analysis of oncologic and functional outcomes after robot-assisted radical cystectomy. Eur Urol 2015; 67: 402.

136. Shabsigh A, Korets R, Vora KC et al: Defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. Eur Urol 2009; 55: 164.

137. Lowrance WT, Rumohr JA, Chang SS et al: Contemporary open radical cystectomy: analysis of perioperative outcomes. J Urol 2008; 179: 1313.

138. Stimson CJ, Chang SS, Barocas DA et al: Early and late perioperative outcomes following radical cystectomy: 90-day readmissions, morbidity and mortality in a contemporary series. J Urol 2010; 184: 1296.

139. Hu M, Jacobs BL, Montgomery JS et al: Sharpening the focus on causes and timing of readmission after radical cystectomy for bladder cancer. Cancer 2014; 120: 1409.

140. Gaya JM, Matulay J, Badalato GM et al: The role of preoperative prostatic urethral biopsy in clinical decision-making at the time of radical cystectomy. Can J Urol 2014; 21: 7228.

141. Kates M, Ball MW, Chappidi MR et al: Accuracy of urethral frozen section during radical cystectomy for bladder cancer. Urol Oncol 2016; 34: 532.

142. Schoenberg MP, Walsh PC, Breazeale DR et al: Local recurrence and survival following nerve sparing radical cystoprostatectomy for bladder cancer: 10-year follow-up. J Urol 1996; 155: 490.

143. Bhatta Dhar N, Kessler TM, Mills RD et al: Nerve-sparing radical cystectomy and orthotopic bladder replacement in female patients. Eur Urol 2007; 52: 1006.

144. Salem H and El-Mazny A: Primary and secondary malignant involvement of gynaecological organs at radical cystectomy for bladder cancer: review of literature and retrospective analysis of 360 cases. J Obstet Gynaecol 2012; 32: 590.

145. Jacobs BL, Daignault S, Lee CT et al: Prostate capsule sparing versus nerve sparing radical cystectomy for bladder cancer: results of a randomized, controlled trial. J Urol 2015; 193: 64.

146. Hautmann RE, Abol-Enein H, Davidsson T et al: ICUD-EAU International Consultation on Bladder Cancer 2012: Urinary Diversion 2013; 63: 67.

147. Madersbacher S, Schmidt J, Eberle J et al: Long-term outcome of ileal conduit diversion. J Urol 2003; 169: 985.

148. Ghosh A and Somani BK: Recent trends in postcystectomy health-related quality of life (qol) favors neobladder diversion: systematic review of the literature. Urology 2016; 93: 22.

149. Philip J, Manikandan R, Venugopal S et al: Orthotopic neobladder versus ileal conduit urinary diversion after cystectomy--a quality-of-life based comparison. Ann R Coll Surg Engl 2009; 91: 565.

150. Hussein Al Awamlh Al B, Wang LC, Nguyen DP et al: Is continent cutaneous urinary diversion a suitable alternative to orthotopic bladder substitute and ileal conduit after cystectomy? BJU Int 2015; 116: 805.

151.Chan Y, Fisher P, Tilki D et al: Urethral recurrence after cystectomy: current preventative measures, diagnosis and management. BJU Int 2016; 117: 563.

152. Stein JP, Clark P, Miranda G et al: Urethral tumor recurrence following cystectomy and urinary diversion: clinical and pathological characteristics in 768 male patients. J Urol 2005; 173: 1163.

153. Kanaroglou A and Shayegan B: Management of the urethra in urothelial bladder cancer. Can Urol Assoc J 2009; 3: S211.

154. Wu SD, Simma-Chang V and Stein JP: Pathologic guidelines for orthotopic urinary diversion in women with bladder cancer: a review of the literature. Rev Urol 2006; 8: 54.

155. Lebret T, Hervé JM, Barré P et al: Urethral recurrence of transitional cell carcinoma of the bladder. Predictive value of preoperative latero-montanal biopsies and urethral frozen sections during prostatocystectomy. Eur Urol 1998; 33: 170.

156. Stein JP, Penson DF, Wu SD et al: Pathological guidelines for orthotopic urinary diversion in women with bladder cancer: a review of the literature. J Urol 2007; 178: 756.

157. Chen ME, Pisters LL, Malpica A et al: Risk of urethral, vaginal and cervical involvement in patients undergoing radical cystectomy for bladder cancer: results of a contemporary cystectomy series from M. D. Anderson Cancer Center. J Urol 1997; 157: 2120.

158. Collins JW, Patel H, Adding C et al: Enhanced recovery after robot-assisted radical cystectomy: EAU Robotic Urology Section Scientific Working Group consensus view. Eur Urol 2016. 70: 649.

159. Karl A, Staehler M, Bauer R et al: Malnutrition and clinical outcome in urological patients. Eur J Med Res 2011; 16: 469.

160. Gregg JR, Cookson MS, Phillips S et al: Effect of preoperative nutritional deficiency on mortality after radical cystectomy for bladder cancer. J Urol 2011; 185: 90.

161. Hemal S, Krane LS, Richards KA et al: Risk factors for infectious readmissions following radical cystectomy: results from a prospective multicenter dataset. Therapeutic Advances in Urology 2016; 8: 167.

162. Crivelli JJ, Xylinas E, Kluth LA et al: Effect of smoking on outcomes of urothelial carcinoma: a systematic review of the literature. Eur Urol 2014; 65: 742.

163. Cumberbatch MG, Rota M, Catto JWF et al: The role of tobacco smoke in bladder and kidney carcinogenesis: a comparison of exposures and meta-analysis of incidence and mortality risks. Eur Urol 2016; 70: 458.

164.Güenaga KF, Matos D and Wille-Jørgensen P: Mechanical bowel preparation for elective colorectal surgery. Cochrane Database Syst Rev 2011: CD001544.

165. Contant CME, Hop WCJ, van't Sant HP et al: Mechanical bowel preparation for elective colorectal surgery: a multicentre randomised trial. Lancet 2007; 370: 2112.

166. Kiran RP, Murray AC, Chiuzan C et al: Combined preoperative mechanical bowel preparation with oral antibiotics significantly reduces surgical site infection, anastomotic leak, and ileus after colorectal surgery. Ann Surg 2015; 262: 416.

167. Morris MS, Graham LA, Chu DI et al: Oral antibiotic bowel preparation significantly reduces surgical site infection rates and readmission rates in elective colorectal surgery. Ann Surg 2015; 261: 1034.

168. Hashad MME, Atta M, Elabbady A et al: Safety of no bowel preparation before ileal urinary diversion. BJU Int 2012; 110: E1109.

169. Large MC, Kiriluk KJ, DeCastro GJ et al: The impact of mechanical bowel preparation on postoperative complications for patients undergoing cystectomy and urinary diversion. J Urol 2012; 188: 1801.

170. Gustafsson UO, Scott MJ, Schwenk W et al: Guidelines for perioperative care in elective colonic surgery: Enhanced Recovery After Surgery (ERAS(®)) Society recommendations. World J Surg 2013; 37: 259.

171. Bilku DK, Dennison AR, Hall TC et al: Role of preoperative carbohydrate loading: a systematic review. Ann R Coll Surg Engl 2014; 96: 15.

172. Carson JL, Grossman BJ, Kleinman S et al: Red blood cell transfusion: a clinical practice guideline from the AABB*. Ann Intern Med 2012; 157: 49.

173. Linder BJ, Frank I, Cheville JC et al: The impact of perioperative blood transfusion on cancer recurrence and survival following radical cystectomy. Eur Urol 2013; 63: 839.

174. Morgan T, Barocas DA, Chang SS et al: The relationship between perioperative blood transfusion and overall mortality in patients undergoing radical cystectomy for bladder cancer. Urol Oncol 2013; 31: 871.

175. Chalfin HJ, Liu JJ, Gandhi N et al: Blood transfusion is associated with increased perioperative morbidity and adverse oncologic outcomes in bladder cancer patients receiving neoadjuvant chemotherapy and radical cystectomy. Ann Surg Oncol 2016; 23: 2715.

176. Xu W, Daneshmand S, Bazargani ST et al: Postoperative pain management after radical cystectomy: comparing traditional versus enhanced recovery protocol pathway. J Urol 2015; 194: 1209.

177. Forrest JB, Clemens JQ, Finamore P et al: AUA Best Practice Statement for the prevention of deep vein thrombosis in patients undergoing urologic surgery. J Urol 2009; 181: 1170.

178. Collins R, Scrimgeour A, Yusuf S et al: Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med 1988; 318: 1162.

179. Bergqvist D: Low molecular weight heparin for the prevention of venous thromboembolism after abdominal surgery. Br J Surg 2004; 91: 965.

180. Geerts WH, Bergqvist D, Pineo GF et al: Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th.Edition). Chest 2008; 133: 381S.

181. Jacobs JJ, Mont MA, Bozic KJ et al: American Academy of Orthopaedic Surgeons clinical practice guideline on: preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Bone Joint Surg Am 2012; 94: 746.

182. Rasmussen MS, Jørgensen LN and Wille-Jørgensen P: Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery. Cochrane Database Syst Rev 2009: CD004318.

183. Forster R and Stewart M: Anticoagulants (extended duration) for prevention of venous thromboembolism following total hip or knee replacement or hip fracture repair. Cochrane Database Syst Rev 2016; 3: CD004179.

184. Kauf TL, Svatek RS, Amiel G et al: Alvimopan, a peripherally acting μ-opioid receptor antagonist, is associated with reduced costs after radical cystectomy: economic analysis of a phase 4 randomized, controlled trial. J Urol 2014; 191: 1721.

185. Lee CT, Chang SS, Kamat AM et al: Alvimopan accelerates gastrointestinal recovery after radical cystectomy: a multicenter randomized placebo-controlled trial. Eur Urol 2014; 66: 265.

186. Vaughan-Shaw PG, Fecher IC, Harris S et al: A meta-analysis of the effectiveness of the opioid receptor antagonist alvimopan in reducing hospital length of stay and time to GI recovery in patients enrolled in a standardized accelerated recovery program after abdominal surgery. Dis Colon Rectum 2012; 55: 611.

187. Chaudhri S, Brown L, Hassan I et al: Preoperative intensive, community-based vs. traditional stoma education: a randomized, controlled trial. Dis Colon Rectum 2005; 48: 504.

188. Colwell JC and Gray M: Does preoperative teaching and stoma site marking affect surgical outcomes in patients undergoing ostomy surgery? J Wound Ostomy Continence Nurs 2007; 34: 492.

189. Leissner J, Ghoneim MA, Abol-Enein H et al: Extended radical lymphadenectomy in patients with urothelial bladder cancer: results of a prospective multicenter study. J Urol 2004;171:139.

190. Vazina A, Dugi D, Shariat SF et al: Stage specific lymph node metastasis mapping in radical cystectomy specimens. J Urol 2004;171:1830.

191. Abdollah F, Sun M, Schmitges J et al: Stage-specific impact of pelvic lymph node dissection on survival in patients with non-metastatic bladder cancer treated with radical cystectomy. BJU Int 212; 109: 1147.

192. Herr HW, Bochner BH, Dalbagni G et al: Impact of the number of lymph nodes retrieved on outcome in patients with muscle invasive bladder cancer. J Urol 202; 167: 1295.

193. Konety BR, Joslyn SA and O'Donnell MA: Extent of pelvic lymphadenectomy and its impact on outcome in patients diagnosed with bladder cancer: analysis of data from the Surveillance, Epidemiology and End Results Program data base. J Urol 2003; 169: 946.

194. Shirotake S, Kikuchi E, Matsumoto K et al: Role of pelvic lymph node dissection in lymph node-negative patients with invasive bladder cancer. Jpn J Clin Oncol 2010; 40: 247.

195. Fahmy N, Aprikian A, Tanguay S et al: Practice patterns and recurrence after partial cystectomy for bladder cancer. World J Urol 2010; 28: 419.

196. Capitanio U, Isbarn H, Shariat SF et al: Partial cystectomy does not undermine cancer control in appropriately selected patients with urothelial carcinoma of the bladder: a population-based matched analysist. Urology 2009; 74: 858.

197. Amin MB, Edge S, Greene F et al: AJCC Cancer Staging Manual. 8 ed: Springer International Publishing. 2017.

198. Bochner BH, Cho D, Herr HW et al: Prospectively packaged lymph node dissections with radical cystectomy: evaluation of node count variability and node mapping. J Urol 2004; 172: 1286.

199. Herr HW, Faulkner JR, Grossman HB et al: Surgical factors influence bladder cancer outcomes: a cooperative group report. J Clin Oncol 2004; 22: 2781.

200. Brossner C, Pycha A, Toth A et al: Does extended lymphadenectomy increase the morbidity of radical cystectomy? BJU Int 2004; 93: 64.

201. Brunocilla E, Pernetti R, Schiavina R et al: The number of nodes removed as well as the template of the dissection is independently correlated to cancer-specific survival after radical cystectomy for muscle-invasive bladder cancer. Int Urol Nephrol 2013; 45: 711.

202. Dhar NB, Klein EA, Reuther AM et al: Outcome after radical cystectomy with limited or extended pelvic lymph node dissection. J Urol 2008; 179: 873.

203. Leissner J, Hohenfellner R, Thuroff JW et al: Lymphadenectomy in patients with transitional cell carcinoma of the urinary bladder; significance for staging and prognosis. BJU Int 2000; 85: 817.

204. Poulsen AL, Horn T and Steven K: Radical cystectomy: extending the limits of pelvic lymph node dissection improves survival for patients with bladder cancer confined to the bladder wall. J Urol 1998; 160: 2015.

205. Zehnder P, Studer UE, Skinner EC et al: Super extended versus extended pelvic lymph node dissection in patients undergoing radical cystectomy for bladder cancer: a comparative study. J Urol 2011; 186: 1261.

206. Simone G, Papalia R, Ferriero M et al: Stage-specific impact of extended versus standard pelvic lymph node dissection in radical cystectomy. Int J Urol 2013; 20: 390.

207. Morgan TM, Barocas DA, Penson DF et al: Lymph node yield at radical cystectomy predicts mortality in node-negative and not node-positive patients. Urology 2012; 80: 632.

208. Siemens DR, Mackillop WJ, Peng Y et al: Lymph node counts are valid indicators of the quality of surgical care in bladder cancer: a population-based study. Urol Oncol 2015; 33: 425.e15.

209. Koppie TM, Vickers AJ, Vora K et al: Standardization of pelvic lymphadenectomy performed at radical cystectomy: can we establish a minimum number of lymph nodes that should be removed? Cancer 2006; 107: 2368.

210. Stein JP, Cai J, Groshen S et al: Risk factors for patients with pelvic lymph node metastases following radical cystectomy with en bloc pelvic lymphadenectomy: concept of lymph node density. J Urol 2003; 170: 35.

211. Wright JL, Lin DW and Porter MP: The association between extent of lymphadenectomy and survival among patients with lymph node metastases undergoing radical cystectomy. Cancer 2008; 112: 2401.

212. Froehner M, Novotny V, Heberling U et al: Relationship of the number of removed lymph nodes to bladder cancer and competing mortality after radical cystectomy. Eur Urol 2014; 66: 987.

213. Kaufman DS, Winter KA, Shipley WU et al: The initial results in muscle-invading bladder cancer of RTOG 95-06: a phase I/II trial of transurethral surgery plus radiation therapy with concurrent cisplatin and 5-fluorouracil followed by selective bladder preservation or cystectomy depending on initial response. Oncologist 2000; 5:471.

214. Hagan MP, Winter KA, Kaufman DS et al: RTOG 97-06: initial report of a phase I-II trial of selective bladder conservation using TURBT, twice-daily accelerated irradiation sensitized with cisplatin, and adjuvant MCV combination chemotherapy. Int J Radiat Oncol Biol Phys 2003; 57:665.

215. Kaufman DS, Winter KA, Shipley WU et al: Phase I-II RTOG study (99-06) of patients with muscle-invasive bladder cancer undergoing transurethral surgery, paclitaxel, cisplatin, and twice-daily radiotherapy followed by selective bladder preservation or radical cystectomy and adjuvant chemotherapy. Urology 2009; 73:833.

216. Herr HW: Outcome of patients who refuse cystectomy after receiving neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol 2008; 54: 126.

217. Herr HW, Bajorin DF and Scher HI: Neoadjuvant chemotherapy and bladder-sparing surgery for invasive bladder cancer: ten-year outcome. J Clin Oncol 1998; 16: 1298.

218. Holzbeierlein JM, Lopez-Corona E, Bochner BH et al: Partial cystectomy: a contemporary review of the Memorial Sloan-Kettering Cancer Center experience and recommendations for patient selection. J Urol 2004; 172: 878.

219. Kassouf W, Swanson D, Kamat AM et al: Partial cystectomy for muscle invasive urothelial carcinoma of the bladder: a contemporary review of the M.D. Anderson Cancer Center experience. J Urol 2006; 175: 2058.

220. Herr HW. Transurethral resection of muscle-invasive bladder cancer: 10-year outcome. J Clin Oncol 2001;19:89.

221. Herr HW, Bajorin DF and Scher HI: Neoadjuvant chemotherapy and bladder-sparing surgery for invasive bladder cancer: ten-year outcome. J Clin Oncol 1998; 16: 1298.

222. Duncan W and Quilty PM: The results of a series of 963 patients with transitional cell carcinoma of the urinary bladder primarily treated by radical megavoltage x-ray therapy. Radiother Oncol 1986; 7: 299.

223. Blandy JP, Jenkins BJ, Fowler CG et al: Radical radiotherapy and salvage cystectomy for T2/3 cancer of the bladder. Prog Clin Biol Res 1988; 260: 447.

224. Jenkins BJ, Caulfield MJ, Fowler CG et al: Reappraisal of the role of radical radiotherapy and salvage cystectomy in the treatment of invasive (T2/T3) bladder cancer. Br J Urol 1988; 62: 342.

225. Gospodarowicz MK, Rider WD, Keen CW et al: Bladder cancer: long term follow-up results of patients treated with radical radiation. Clin Oncol 1991; 3: 155.

226. Jahnson S, Pedersen J and Westman G: Bladder carcinoma - a 20-year review of radical irradiation therapy. Radiother Oncol 1991; 22: 111.

227. Fossa SD, Waehre H, Aass N et al: Bladder cancer definitive radiation therapy of muscle-invasive bladder cancer. A retrospective analysis of 317 patients. Cancer 1993; 72: 3036.

228. Rozan R, Albuisson E, Donnarieix D et al: Interstitial iridium-192 for bladder cancer (a multicentric survey: 205 patients). Int J Radiat Oncol Biol Phys 1992; 24:469.

229. Pernot M, Hubert J, Guillemin F et al: Combined surgery and brachytherapy in the treatment of some cancers of the bladder (partial cystectomy and interstitial iridium-192). Radiother Oncol 1996; 38:115.

230. Pos F, Horenblas S, Dom P et al: Organ preservation in invasive bladder cancer: brachytherapy, an alternative to cystectomy and combined modality treatment? Int J Radiat Oncol Biol Phys 2005; 61:678.

231. Mak R, Hunt D, Shipley W et al: Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined modality therapy: a pooled analysis of RTOG protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol 2014; 32:3801.

232. Efstathiou JA, Spiegel DY, Shipley WU et al: Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience. Eur Urol 2012; 61: 705.

233. Eswara JR, Efstathiou JA, Heney NM et al: Complications and long-term results of salvage cystectomy after failed bladder sparing therapy for muscle invasive bladder cancer. J Urol 2012; 187:463.

234. James ND, Hussain SA, Hall E et al: Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012; 366:1477.

235. Coppin C, Gospodarowicz M, James K et al: Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1996; 14: 2901.

236. Choudhury A, Swindell R, Logue JP et al: Phase II study of conformal hypofractionated radiotherapy with concurrent gemcitabine in muscle-invasive bladder cancer. J Clin Oncol. 2011; 29:733.

237. Herman JM, Smith DC, Montie J et al: Prospective quality of life assessment in patients receiving concurrent gemcitabine and radiotherapy as a bladder preservation strategy. Urology 2004; 64:69.

238. Mitin T, Hunt D, Shipley WU et al: Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol 2013; 14:863.

239. Zietman AL, Grocela J, Zehr E et al: Selective bladder conservation using transurethral resection, chemotherapy, and radiation: management and consequences of Ta, T1, and Tis recurrence within the retained bladder. Urology 2001;58:380.

240. Picozzi S, Ricci C, Gaeta M et al: Upper urinary tract recurrence following radical cystectomy for bladder cancer: a meta-analysis on 13,185 patients. J Urol 2012; 188: 2046.

241. Sanderson KM, Cai J, Miranda G et al: Upper tract urothelial recurrence following radical cystectomy for transitional cell carcinoma of the bladder: an analysis of 1,069 patients with 10-year follow-up. J Urol 2007; 177: 2088.

242. Tran W, Serio AM, Raj GV et al: Longitudinal risk of upper tract recurrence following radical cystectomy for urothelial cancer and the potential implications for long-term surveillance. J Urol 2008; 179: 96.

243. Hall MC, Koch MO and McDougal WS: Metabolic consequences of urinary diversion through intestinal segments. Urol Clin North Am 1991; 18:725.

244. Harraz AM, Mosbah A, El-Assmy A et al: Renal function evaluation in patients undergoing orthotopic bladder substitution: a systematic review of literature. BJU Int 2014; 114: 484.

245. Amini E and Djaladat H: Long-term complications of urinary diversion. Curr Opin Urol 2015; 25:570.

246. Krajewski W, Piszczek R, Krajewska M et al: Urinary diversion metabolic complications - underestimated problem. Adv Clin Exp Med 2014; 23: 633.

247. Tan WS, Lamb BW, and Kelley D: Complications of radical cystectomy and orthotopic reconstruction. Adv Urol 2015; 2015: 323157.

248. Van der Aa, F, Joniau S, Van Den Branden VD et al: Metabolic changes after urinary diversion. Adv Urol 2011; 2011.

249. Volkmer BG, Schnoeller T, Kuefer R et al: Upper urinary tract recurrence after radical cystectomy for bladder cancer--who is at risk? J Urol 2009; 182:2632.

250. Raj GV, Bochner BH, Serio AM et al: Natural history of positive urinary cytology after radical cystectomy. J Urol 2006; 176:2000.

251. Sullivan PS, Nooraie F, Sanchez H et al: Comparison of Immuno-Cyt, UroVysion, and urine cytology in detection of recurrent urothelial carcinoma: a “split-sample” study. Cancer (Cancer Cytopathol) 2009;117:167.

252. Dimashkieh H, Wolff DJ, Smith TM et al: Evaluation of Urovysion and cytology for bladder cancer detection: a study of 1835 paired urine samples with clinical and histologic correlation. Cancer (Cancer Cytopathol). 2013; 121:591.

253. Chang SS, Boorjian SA, Chou R et al: Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO Guideline. J Urol 2016; 196: 1021.

254. Sherwood JB and Sagalowsky AI: The diagnosis and treatment of urethral recurrence after radical cystectomy. Urol Oncol 2006; 24: 356.

255. Clark PE and Hall MC: Contemporary management of the urethra in patients after radical cystectomy for bladder cancer. Urol Clin North Am.2005; 32: 199.

256. Tobisu KI, Tanaka Y, Mizutani T et al: Transitional cell carcinoma of the urethra in men following cystectomy for bladder cancer: Multivariate analysis for risk factors. J Urol 1991; 146:1551.

257. Nieder AM, Sved PD, Gomez P et al: Urethral recurrence after cystoprostatectomy: implications for urinary diversion and monitoring. Urology 2004; 64:950.

258. Knapik JA and Murphy WM: Urethral wash cytopathology for monitoring patients after cystoprostatectomy with urinary diversion. Cancer 2003; 99:352.

259. Lin DW, Herr HW and Dalbagni G: Value of urethral wash cytology in the retained male urethra after radical cystoprostatectomy. J Urol 2003;169:961.

260. Boorjian SA, Kim SP, Weight CJ et al: Risk factors and outcomes of urethral recurrence following radical cystectomy. Eur Urol 2011; 60: 1266.

261. Bassett JC, Gore JL, Chi AC et al. Impact of a bladder cancer diagnosis on smoking behavior. J Clin Oncol, 2012; 30:1871.

262.Karam-Hage M, Cinciripini P and Gritz E: Tobacco use and cessation for cancer survivors: an overview for clinicians. CA Cancer J Clin 2014; 64: 272-90.

263. PDQ Supportive and Palliative Care Editorial Board. Smoking in Cancer Care (PDQ®): Health Professional Version. 2014 Jun 20. In: PDQ Cancer Information Summaries Internet. Bethesda (MD): National Cancer Institute (US); 2002.

264. PDQ Supportive and Palliative Care Editorial Board. Nutrition in Cancer Care (PDQ®): Health Professional Version. 2016 Jan 8. In: PDQ Cancer Information Summaries Internet. Bethesda (MD): National Cancer Institute (US); 2016.

265. Siefker-Radtke AO, Kamat AM, Grossman HB et al: Phase II clinical trial of neoadjuvant alternating doublet chemotherapy with ifosfamide/doxorubicin and etoposide/cisplatin in small-cell urothelial cancer. J Clin Oncol 2009; 27: 2592.

266. Patel SG, Stimson CH, Zaid HB et al: Locoregional small cell carcinoma of the bladder: clinical characteristics and treatment patterns. J Urol 2014; 191: 329. 

267. Choong NW, Quevedo JF and Kaur JS: Small cell carcinoma of the urinary bladder. The Mayo Clinic experience. Cancer 2005; 103: 1172. 

268. Quek ML, Nichols PW, Yamzon J et al: Radical cystectomy for primary neuroendocrine tumors of the bladder: the university of southern California experience. J Urol 2005; 174: 93. 

269. Kaushik D, Frank I, Boorjian SA et al: Long-term results of radical cystectomy and role of adjuvant chemotherapy for small cell carcinoma of the bladder. Int J Urol 2015; 22: 549.

270. Siefker-Radtke AO, Dinney CP, Abrahams NA et al: Evidence supporting preoperative chemotherapy for small cell carcinoma of the bladder: a retrospective review of the M.D. Anderson cancer experience. J Urol 2004; 172: 481.

271. Eswara JR, Heney JM, Wu CL et al: Long-term outcomes of organ preservation in patients with small cell carcinoma of the bladder. Urol Int 2015; 94:401.

272. Mattes MD, Kan CC, Dalbagni G et al: External beam radiation therapy for small cell carcinoma of the urinary bladder. Pract Radiat Oncol 2015; 5:e17.

273. Meijer RP, Meinhardt W, van der Poel HG et al: Local control rate and prognosis after sequential chemoradiation for small cell carcinoma of the bladder. Int J Urol 2013; 20:778.

274. Bryant CM, Dang LH, Stechmiller BK et al: Treatment of small cell carcinoma of the bladder with chemotherapy and radiation after transurethral resection of a bladder tumor. Am J Clin Oncol 2016; 39: 69.

275. Meeks JJ, Taylor JM, Matsushita K et al: Pathological response to neoadjuvant chemotherapy for muscle-invasive micropapillary bladder cancer. BJU Int 2013; 111: E325.

276. Kamat AM, Dinney CP, Gee JR et al: Micropapillary bladder cancer: a review of the University of Texas M.D. Anderson Cancer Center experience with 100 consecutive patients. Cancer 2007; 110: 62.

277. Ghoneim IA, Miocinovic R, Stephenson AJ et al: Neoadjuvant systemic therapy or early cystectomy? Single-center analysis of outcomes after therapy for patients with clinically localized micropapillary urothelial carcinoma of the bladder. Urology 2011; 77: 867.

 

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